The pharmacological blockade of P2X4 receptor as a viable approach to manage visceral pain in a rat model of colitis.
J Drug Target
; 32(8): 953-963, 2024 Sep.
Article
in En
| MEDLINE
| ID: mdl-38864378
ABSTRACT
Nowadays, the pharmacological management of visceral hypersensitivity associated with colitis is ineffective. In this context, targeting purinergic P2X4 receptor (P2X4R), which can modulate visceral pain transmission, could represent a promising therapeutic strategy. Herein, we tested the pain-relieving effect of two novel and selective P2X4R antagonists (NC-2600 and NP-1815-PX) in a murine model of DNBS-induced colitis and investigated the mechanisms underlying their effect. Tested drugs and dexamethasone (DEX) were administered orally, two days after colitis induction. Treatment with tested drugs and DEX improved tissue inflammatory parameters (body weight, spleen weight, macroscopic damage, TNF and IL-1ß levels) in DNBS-rats. In addition, NC-2600 and NP-1815-PX attenuated visceral pain better than DEX and prevented the reduction of occludin expression. In in vitro studies, treatment of CaCo2 cells with supernatant from THP-1 cells, previously treated with LPS plus ATP, reduced the expression of tight junctions protein. By contrast, CaCo2 cells treated with supernatant from THP-1 cells, previously incubated with tested drugs, counteracted the reduction of tight junctions due to the inhibition of P2X4R/NLRP3/IL-1ß axis. In conclusion, these results suggest that the direct and selective inhibition of P2X4R represents a viable approach for the management of visceral pain associated with colitis via NLRP3/IL-1ß axis inhibition.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colitis
/
Disease Models, Animal
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Receptors, Purinergic P2X4
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Purinergic P2X Receptor Antagonists
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Visceral Pain
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
J Drug Target
Journal subject:
FARMACOLOGIA
Year:
2024
Document type:
Article
Affiliation country:
Italy